Dyslipoproteinemia (combined hypercholesterolemia-hypertriglyceridemia), low HDL-cholesterol), obesity (in particular upper body obesity), impaired glucose tolerance (IGT) leading to noninsulin-dependent diabetes mellitus (NIDDM)) and essential hypertension are common diseases that afflict individuals living in Westernized societies. Being initiated and linked through hyper-insulinemia these four diseases often coexist and precipitate independently as well as synergistically atherosclerotic vascular disease leading to coronary heart disease. The incidence of the Deadly Quartet (Syndrome-X, Metabolic Syndrome) comprising the four diseases increases as the population ages and by 70 years of age reaches epidemic proportions. Combatting the individual categories of the Deadly Quartet as well as offering a whollystic therapeutic approach to the Syndrome is considered one of the most important challenges of medicine in affluent Westernized society.
Many hypercholesterolemic/hypertriglyceridemic individuals turn out as low- or non-responders to dietary measures and therefore are candidates for long-term treatment with hypolipidemic drugs. HMG-CoA reductase inhibitors and bile acid sequestrants designed to upregulate the LDL receptor are very effective in isolated hyper-cholesterolemia. However, both are ineffective in reducing plasma triglycerides and poorly effective in increasing plasma HDL, thus being short of offering an adequate treatment mode for combined hypertriglyceridemia-hypercholesterolemia (which comprise of &gt;70% of dyslipoproteinemic patients) or for isolated hypertriglyceridemia with reduced plasma HDL, as well as for the postprandial chylomicrons-rich phase realized now as an independent risk for atherosclerotic cardiovascular disease. Isolated hyper-triglyceridemia may however be treated with either nicotinic acid or drugs of the fibrate family. However, the compliance for nicotinic acid is very poor and the advantage of fibrate drugs in lowering overall mortality has been seriously questioned since the exhaustive WHO clofibrate study. Also, nicotinic acid is ineffective while fibrate drugs are only poorly effective in reducing plasma cholesterol, thus leaving the combined hypertriglyceridemic-hypercholesterolemic patient with the only choice of a combination treatment mode (e.g., HMG-CoA reductase inhibitor/nicotinic acid). Weight reduction measures are essentially based on promoting dietary or behavioral means for reducing weight. However, most obese individuals turn out to respond inadequately to dietary or behavioral measures, especially if examined over long time periods. The chances for 5-year maintenance of weight reduction initiated by dietary and behavior modifications are less than 10%. This overwhelming failure is mainly metabolic, since the decrease in weight as a result of dieting is always accompanied by a decrease in basal metabolic rate and overall energy expenditure, thus forcing the dieting obese patient into a genuine deadlock. Antiobesity drugs based on modulating energy intake are currently based on anorectics designed to depress the hypothalamic satiety center. These drugs are reported to be ineffective in the medium and long range and some may induce primary pulmonary hypertension. Similarly, no antiobesity drugs are presently available based on modulating total body calorie expenditure while allowing free access to calorie consumption. Peripherally acting thermogenic .beta.3-adrenergic agonists are selected on the basis of their capacity to stimulate brown adipose tissue .beta.-adreno receptors and may indeed induce thermogenesis in rodents. However, the efficacy of such agents in humans while allowing free access to calories is still questionable and their ;broad tissue specificity (e.g., skeletal muscle, myocardium, colon) may be expected to result in nonspecific-adrenergic-induced effects.
Presently available pharmacological measures for treating IGT and overt NIDDM consist of two oral hypoglycemic drug types which are in use for over 30 years. The sulphonylureas promote pancreatic insulin secretion for coping with peripheral insulin resistance, while biguanides are claimed to improve peripheral insulin action. The popularity of sulphonylurea does result from the old conviction that blood glucose which precipitates the diabetic microvascular disease in retina kidney, nerve and some other tissues should be normalized by all means even at the expense of increased pancreatic insulin secretion. This therapeutic approach was initiated in times when the hyperinsulinemic phase dominating the natural history of the development of NIDDM or the course of obesity-induced IGT was not realized, neither the pathological sequel dictated by sustained hyperinsulinemia. Moreover, the sulphonylurea (similarly to insulin) tend to promote weight gain, thus further promoting insulin resistance and compensatory hyperinsulinemia leading to diabetes-induced macrovascular disease (atherosclerotic cardiovascular disease). Biguanides are claimed to potentiate insulin-mediated glucose disposal with no stimulation of pancreatic insulin secretion. However, the use of biguanides as monotherapy is not unanimously recommended except for the very obese in light of their low therapeutic/toxicity index and the induction of lactic acidosis. During the period of the last ten years, the scientific community became progressively aware of the etiological-pathophysiological linkage between dyslipo-proteinemia, obesity, NIDDM, hypertension, decreased fibrinolysis and some other pathologies (e.g., hyperuricemia), realizing now that the concerned pathologies are just reflections of a unifying Syndrome. Leading to atherosclerotic cardiovascular disease, the Syndrome is realized now to be the major risk factor for mortality and morbidity in Western Societies. Treating the Syndrome pharmacologically calls for an whollystic approach rather than dealing separately with each of its distinct categories. No drug designed alongside these principles is yet available.
.alpha., .omega.-Dialkanoic acids of chain length of 14 20 carbon atoms which are hydrocarbyl substituted on the .beta.,.beta.' carbon atoms, as well as their salts and ester derivatives were disclosed in Bar-Tana U.S. Pat. Nos. 4,634,795, 4,689,344 and 4,711,896 as possessing a hypolipidemic, weight reducing and antidiabetogenic activity. Realizing however that treatment of the Metabolic Syndrome and its related pathologies would require chronic dosing has initiated an exhaustive search for new compounds having a higher efficacy as compared with the previously disclosed .beta.,.beta.'-substituted .alpha.,.omega. dialkanoic acids.